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Lunchtime session. It's the only time uh that any of the speakers were free. Um So minus fish missionaries, one of the doctors um that's co running this course with Rachel. And today we're going to talk about High Court's soul. Um As always, please do. Um Right in the comment section, if you've got any questions, we've got plenty of poll questions to get through today as well. Um And ultimately the sessions um trying to teach the basics of cushion syndrome, how you would investigate it and we're going to run through a few cases. So as I've stated, the aims of my session today is to talk about the clinical features of cushion syndrome. We're gonna have a quick recap of the physiology about cortisol production. But mainly I want to focus on the myriad of investigations and management options in cushion syndrome. So, ultimately, um Cushing's syndrome is a clinical manifestation of excess cortisol. That is what we're going to be talking about today. Um I just wanted to see what people thought in terms of um what the most common causes of Cushing's syndrome is in the UK. So what I've decided to do is ask you to vote on that. So just choose an answer uh um and see what we get. Um I'm gonna give you a couple of seconds to think about that. People who have rather slide me have a clear of the answer already. Um So in the UK as worldwide, um the most common cause is exogenous steroid use. So, um for asthma for rheumatoid arthritis, um it is the biggest cause. So when you take your histories for a patient that you suspect may have cushion syndrome, you must take a detailed history about all steroid use, whether it's creams, inhalers or tablets. Now, there's a lot of um confusion around the terminology about cushions disease and cushion syndrome. So remember cushion syndrome, it's just the clinical manifestation of excess cortisol. It could be for any cause, writes cushions disease is where there's a pituitary adenoma producing ACTH, which results in excess cause cell production from the adrenal glands. The most important thing to take away from this talk is that Cushing's syndrome is hard to diagnose, it's hard to investigate. But I hope by the end of this talk, I can reveal or show project, show you some of the key clinical features that we can use to increase our clinical yield and clinical suspicion. Just a quick talk about the H P A axis. We'll keep coming back to this when I go through the investigations that is used in Cushing's Syndrome. Um So as you all know, the hypothalamus releases, um, crh, which feeds into pituitary and the pituitary releases um, several pituitary hormones. But the one we're going to focus on today is the ACTH hormone which then stimulates cortisol, cortisol, then has a negative feedback. So this is all about feedback loops at the, both the pituitary and the hypothalamus level to reduce the production of both crh and A C A T A T H. There are many other hormones and things that could trigger this H P axis and also suppress the H P axis. We won't cover all of them, but we will think about how that may impact when it comes to our diagnosis of cushion syndrome. The second bit of physiology that I wanted to recap is how is cortisol carried in the blood on the majority of it is carried by cortisol binding globulin. Um In American textbooks, you can sometimes see it was referred as transporting. It is also carried by albums about 10%. And freak Ortel only makes up about somewhere between 4 to 8%. I put down 5 to 10% in slides. Now, that is very important to remember that because when we measure or do blood tests for cord sell, we get the whole lot, we get the bound cortisol and also the free cortisol. However, the bodies currency is measured in free cortisol. So what we're seeing is slightly different to how the body sees it and the way we interpret a test, therefore, um, must take into account for that. And we'll come onto that again when we talk about, go through all the investigations that we can do for cushion syndrome. So I've decided that we'll do this by cases. So we'll loosely hold and some talk about some cases. Um, and we'll talk about around the cases. Like I said, if there are any questions at any point, do put it on the, on the messages, I'll see if I can have a spot of it and answer as we go along. So this is, these are all real cases that I've seen my experience as um an endocrine doctor, um are working the endocrine award. Um, so Mr M is a 45 year old gentleman and he was feeling, he felt quite weak and tired for the last three months. This is not an uncommon presentation. Everyone feels tired, he reports headaches, increase your new frequency, but can't really offer anything else in the history. I don't know if anyone has any thoughts at this perspective point in time, I'm just gonna present the past medical history of drug history. So apart from poorly controlled hypertension, he's never been diagnosed with diabetes or any other medical conditions. He's on four medications for his BP, amLODIPine, Ramipril, and death wide and Doxazosin. And it still hasn't affected his BP and more concerning his family's history is quite strong for his previous strokes. Both his father and grandfather have had strokes. He works as a data analyst. He is a social drinker, so it doesn't accessory drink any smokes one pack a day, any thoughts or any ideas of what this could be. I appreciate. This is a talk about kitchen syndrome. But any other questions you would want to ask or think it's important to ask. Mr M. At this point in time, please do um right out on the chat. If you had any thoughts, I didn't catch that. Could you try again? Okay. So I'll let you right in the thoughts if there's anything, if there's anything else in the thoughts that you have had an idea of, um but key points in the history. So Cushing's syndrome is very tough to diagnose and the reasons why is it can be nonspecific, fatigue and weakness are common symptoms. You have to be specific about weight gain were very good at being specific about weight loss. We ask about how many kilos over how many months, what with cushions you have to go even further. You have to ask about what you eat. What's your diet? How have you tried to lose weight? Do you exercise regularly? Have you tried any dieting programs? Have you tried any exercise programs? And if people are still gaining weight, despite all of these interventions, that's more convincing than not, we've already talked about asking about any steroid use. So remember, creams inhalers also contribute and I absorbed systemically, ask about OCP use last menstrual period and menstruation this affects um so the OCP and if they're pregnant, uh that affects how you interpret the results because you're caught or binding globulin goes up. Cushing's syndrome also affects periods. So that's the other reason to ask about it, screen for associated symptoms, symptoms that um such as for diabetes and hypertension symptoms and screen for additional uh conditions, ask about skin changes, acne easy breezing hair loss, previous fractures and also asked about smoking and alcohol because that could also impact on the metabolic syndrome that were trying to differentiate cushion syndrome from so onto examination. Now, examination is also non specific in bold. I've highlighted what the endocrine society believes are the most specific signs for high corsa or course all excess, all the other signs are present and common. But they are not specific for cushion syndrome that could be um present in simple obesity in the metabolic syndrome that we've just briefly discussed um in any other causes of hyper authorities. Um for example, so these are not specific or sensitive signs. So purple violations, stri proximal myopathy, aphasia, plethora happen to be the most sensitive signs after them. And even these are not sensitive proximity is present in plenty of hype authorities and patient's purpose. Try a is present in anyone who's gained weight quickly and facial plethora um can be present in many other conditions. So again, we're struggling with the history and examination to get specific signs and specific symptoms. So this is just a purple stripe on the left hand side. And this is a woman who's got facial plethora. You can see some acne in chin and hirsutism and with a faith, faith of I you can also appreciate that she has um some also cervical fat pads and just to take her message, unfortunately, signs of symptoms for Christmas syndrome are not specific or sensitive. Ultimately, when you have these patient's in front of you, you have to think about who you're going to send off for further investigations and who you're going to say while they have a metabolic syndrome or they have simple obesity and they need more time to lose weight, etcetera, or you're going to treat them as undiagnosed or untreated diabetes. So you try and put in or collect as much evidence as you can to try and choose between who gets treated or who gets sent, sent for further investigations and who does not and there's no right or right or wrong answer. Um, but there are some screening tools that can help us choose which ones go further and which ones do not. In our gentleman. We've got a young gentleman who's got uncontrolled hypertension who has symptoms and signs of cushion syndrome. So I'm going to open up to the floor with another poll and ask what is the first diagnostic test that you would order four kitchen syndrome So, uh, let you answer it on the pole. I'll give you about a minute so I can get a few more answers. It's about 15 people. So we're halfway there. I'm just gonna give it a few more seconds for the, see if we can get up to the whole 15. Okay. I'm gonna stop it there. So we have a haven't even split. Well, we have a split of some sort so some people have gone straight for, for the higher dose dexamethasone suppression test. Um I'll come back to that nine AM cortisol. So remember the nine AM CORSO is an excellent test for Addison's for the other diagnosis. Why? Because your cortisol should be high at nine AM. So you're expecting a high level. So that will not be helpful if you're trying to exclude excess cortisol production. Okay. A low dose dexamethasone suppression test that it is the test that we would do straight after we would not do a 24 hour urine collection of metanephric because that's a diagnosis for pheochromocytoma. So that's excess catacomb in uh production. It's not for cortisol. And the high dose dexamethasone suppression test is when you have a diagnosis of cushions syndrome confirmed and you're trying to find the etiology of it. Is it cushions disease or cushion syndrome? Don't worry, we'll go through all the other tests and shortly apart from the 24 hour urine collection, the midnight call. So is the best answer in this group of possibilities just to reiterate that point. So this is a circadian rhythm. A really simplistic diagram. You've got your cortisol levels on the Y axis and you've got data um time during the day on the X axis just plots the graph. So as you can see at nine AM, your quarter levels extremely high. And at 12 a.m. or midnight, your course levels should be undetectable low, you should be asleep at midnight, which is why your course levels should be undetectable. So let's talk about screen tests. Now, the endocrine society um and the International J CM Society have different opinions of what test to use. So the midnight call toll can be quite legislate difficult because how do you get patient's in to say your G P practice or um into the hospital at midnight to make sure you do the test? What if they've been awake longer? You know what if they're wake, sleep, wake cycle has been reversed? What about shift workers is not particularly useful in these patient's because their circadian rhythm is different or affected. 24 hour urine collection quarter collection is an excellent way of screening for uh this condition. So cushion syndrome, um the one of the advantages or main advantages that avoids the problems or issues of including quarter binding globulin called soul. Um In the calculation of cushion syndrome, you normally need at least two separate measurements to confirm or be suspicious of a diagnosis. Um and it's extremely useful in pregnancy because in pregnancy, the hormones, estrogen increase the levels of C B G and therefore your course a levels rise. If you did a simple blood test, the union free coaster will reveal a true answer. Midnight salary, salary record soul has now become a new um test. It is not widely available and the cut offs are not established yet, but it is an up and coming test. And overnight dexamethasone suppression test is a very simple test where you give the patient a tablet to take home and you measure the cortisol levels. The next day, the issues with this test is that it can be affected by other medications. So any other medications that affect the P 4 50 system either induces or inhibitors or if the patient has a malabsorption disorder. So, if they have celiac disease, the dexamethasone doesn't get fully absorbed. And therefore, um, you don't fully have a reliable result. At the end of it, there's also a theoretical risk in case reports of causing a fierce Chromos item, a crisis that is theoretically um, only considered, um based on case reports in the 19 fifties and sixties. So it's not something that's widely seen um, in current practice. However, there's still that concern about giving patient's who you've, you have a reasonable suspicion of a pheochromocyto um, as well as a cushion syndrome. So those are the main screen testers are used in the UK some special considerations. So we talked briefly about a few of these considerations. So we've already talked about pregnancy epilepsy. That's because they have medications that would enhance text message and clearance renal failure. Um, you know, free call soul would not be very useful in these patient's because they won't be producing enough urine. Um in the 24 hours Psychic Cushion syndrome, um would, won't touch on too much in this um session because it's quite a complex diagnosis. But using dexamethasone suppression test, you may miss the diagnosis whereas 24 hour collections may give you a better yield, especially since you will do it on two separate occasions. An adrenal incidentaloma is a diagnosis made on a CT scan. So where a patient is scanned top to toe for a completely different reason and you find an adrenal lesion on that scan, these patient's may have no symptoms or very unclear symptoms. But since you found a lesion, you have to work out whether it's benign malignant and if it's producing any hormones. And this is why it suggests to use the dexamethasone suppression test rather than a free collection because the dexamethasone suppression test has better yield of ruling people in as the urine collection is preferentially is for people that you want to rule out and don't have cushion syndrome. I hope that's clear. And please again, do you ask any questions as we go along through this session? So what I really wanted to focus on it during this talk is about talking about dynamic tests. Now, the principal dining test is very easy. You test whatever hormone that you're interested in before you do the test. If you and if you suspect too much of a hormone. So let's say too much cortisol, you give a medication to suppress it. If it's too low, you try and give a hormone to stimulate it. That's the principle of dynamic tests and they remeasure it after you give this medication. So for High court's so we give Dexa medicine because that was completely suppress course or should completely suppress course of production. Predn insulin does suppress course of production as well. But the issue is that we can't use it in our dynamic test. And that's because it cross reacts the essay leading to unreliable results. So that's why we always use Dexa medicine if anyone was wondering. So let's talk about the first dynamic test we've mentioned and that's the overnight dexamethasone suppression test. So this is the protocol from the end of Bible. This is actually the protocol pretty much nationally if you wanted to do it. Um So it's for patient's that your screening for Christian syndrome, you'll have some suspicion that they may have this uh syndrome. So you give them, give the patient a milligram of Dexa medicine. They could be at home doing this test because all they need to do is just make sure that they take a tablet at 10 o'clock at night, then you ask them to come back or if they in the hospital, you take a blood test at nine o'clock for cortisol. Um You do need to warn them because 1 mg of decks medicine is quite strong for people who don't have cushion syndrome, that they may not be able to sleep overnight and they may feel a bit wide orbiting, you know, excited or delirious a normal level. Should it be undetectable levels? Of course, of the next day. So in most trust that's less than 15 animals. Um of course, so at 9 a.m. the next day, so anything higher, you have not ruled out cushion syndrome. And this is again that HP axis just remember you have normal negative feedback from your quarter on the hypothalamus in the pituitary, your dexa medicine has negative feedback to your hypothalamus and pituitary as well. And that's why you should have no course of production if you had um a normal functioning hyper pathetic pituitary access. So in our case, we did that, we sent him off for an overnight dexamethasone suppression test and we also did a midnight call. So because he was in hospital, both came back high, the question is now you've got these results. What is the next test that you would order? So again, I've put out a poll. I want you to see what you would next order. It's like people a few more minutes again. If anyone has any questions or comments, do please do type them in as well. Um If, if you want me to go over something, I'm more than happy to do so, I'm gonna wait for a couple more responses. Okay. An interest time. I'm going to call it. So the majority of people have gone for a high dose dexamethasone suppression test. No, the first thing to say is that, remember that the overnight X muscle suppression test is a screening tool. It is not perfect. There are obviously some issues with it as we've already discussed. So we would need to make sure that we would confirm the diagnosis first. The high dose XMS, a specialist to differentiate between cushion syndrome and Cushing's disease. So it's trying to find out the etiology of why there's too much cortisol. But we just need to prove that there is excess court's on the first place. The correct answer, the best answer would be a low dose dexamethasone suppression test. Now, in terms of imaging, you always have to in n decline, confirm the biochemical diagnosis before moving onto imaging 24 hour urine, your three quarter collections. A it's a good, good idea. Um But remember the reason why we went for an overnight dexa dexamethasone suppression test is our suspicion of cushion syndrome was higher. We would only want to do a collection to rule it out. But now we've got evidence that that it's there the 24 hour unit called. So wouldn't help us rule it in or out anymore. It would as a test it in itself, it's not beneficial. So the best answer is the low dose dexamethasone suppression test. So this is how you confirm Christian syndrome, you do a low dose dexamethasone suppression test. So on day one at nine o'clock, you take blood for ACTH quarter on other adrenal steroids, that's includes testosterone, um uh D H E S, um etcetera. But we won't need to worry too much about that. I just want to focus on the ACTH and Cortisol patient's take 0.5 mg of dexamethasone every six hours for the next 48 hours. So once you take your blood test that you give them dexamethasone at nine o'clock, then they take it again at three o'clock in the afternoon, nine pm in the evening, three o'clock in the morning and then you, they wake up at nine o'clock and so it continues, you can, if they're in hospital, take blood samples at nine o'clock on the first day, second day and the third day. So after you get the tablets, so you can do it at two plus 24 2 plus 48. Now, the reason why that's traditional is because if they're taking 480.5 mg every six hours for 40 hours, that means they take a total of 2 mg. So 2 mg plus 24 is 24 hours after they first started this protocol and two plus 48 which is what we're really interested in is done 48 hours at the end of the test. And at the end of the test, we take a further course on ACTH level. And what we should be expecting is complete suppression, of course, sell. So again to undetectable levels. Um so less than 50 in our gentleman's case, he has low dose dexamethasone suppression test after 48 hours came back at 200. So that's high. So the question is what would be the next test that you order? I'm gonna let you answer them the pool. Okay. So a reasonable split between high dose dexamethasone suppression test and an MRI pituitary. So 2 to 1 in favor of high dose dexamethasone suppression test. Now let's talk about both of them. So to find the cause of cushion syndrome, traditionally, high dose dexamethasone suppression test was the first test that you would do. Um And the reason why is the pituitary gland will a pituitary cause? So in a pituitary, adenoma will suppress if you give higher doses of dexamethasone compared to other causes. So, otherwise an ectopic A C A T H production on adrenal adenoma. So you can be certain or pretty sure that the pituitary is the reason if it suppresses over the high dose compared to other causes nowadays because the availability of MRI pituitary is great and the sensitivity of MRI pituitary is really high. Many centers preferred to go straight to MRI pituitary as the choice of investigation. So this depends on where you work. The other things to consider is whether the patient symptoms are in keeping with the pituitary cause. Do they have headache? Do they have visual loss? If the ACTH is high, then it's unlikely to be adrenal because they're doing your cushions. Well, it's just production of cortisol and the cortisol production will suppress the pituitary ACTH. You can use the petrol profile to see if any other hormones. Um like TSH or LH and FSH are affected and you can use other steroids which the adrenals producers see if there's a greater production of other steroid hormones at the adrenal level. But ultimately, and eh my pituitary is probably what most centers use. Now it when the suspicion of a pituitary cause of um cushion syndrome is suspected. So that's just um back to the H P access, just remind everyone that if A C T H was the cause, um your ACTH and quarter will both be high. However, if it's adrenal was the cause your ACTH will be suppressed because of the excess cortisol production. Another quite smart way of thinking of investigating this is doing a quarter day curve. I know no one's use that as an answer because it's not widely used. How have some centers, what they do is they insert a Kanye and they take quarter levels regularly throughout the day and you can plot a graph. Now, in pituitary causes of cushion syndrome or excess quarter, you would expect a graph to go up and down quite similar to the circadian rhythm, but it's unpredictable. However, if you had an adrenal course and an adrenal adenoma shunting out cortisol all the time, you would actually expect a quite steady state, of course, whole, not necessarily a flat line that pretty small, narrow margin of course, or regions throughout the day. Again, this is another piece of evidence pointing you to the direction what is causing the excess cortisol. So after you confirm diagnosis, kitchens, you need imaging. Um and as I've said, it was uh directed by other symptoms and ACTH. So if your ACTH is suppressed, you'll proceed on to a imaging of the adrenal glands, either an MRI scan or a CT scan. So here we can see a CT scan. I've got arrows there to point at where the lesion is. So this patient has an adrenal adenoma uh support, which is clearly producing cortisol as this excess hormone. So the question is, how would we manage this patient just for the interest of time, I'll go through management um quickly. So the medical options will be metyraPONE and ketaconazole. This these both are medications that hib it the steroid census pathway at different points. So ketaconazole, the P 4 50 inhibitor. So it stops the entire steroid pathway pretty much metyraPONE is 11 beater HSD inhibitor, they also impact other parts of the pathway, but we won't get bogged down by that. So medical options can slow the production of cortisol. But ultimately, what do you really want to do is take out the lesion and adrenalectomy. Adrenalectomy is the only option. This patient after this will need lifelong replacement of both cortisol and aldosterone in the form of hydrocortisone and fludrocortisone. Before we move on to case too. I wondered if there were any questions about case one or any of the investigations that we've gone through if you do, uh, do put it in the chat. Um I'll try and pick them up. So our second case is a 35 year old female who's presents with Tinus general malaise headache and difficulty losing weight. She's tried multi diets in the past, not helped at all. She said she photos on her phone how she looked like when she was 14 and 15 and what she looks like now on examination, she's got some of those signs that we talked about that were consistent with Cushing's syndrome and you send off some investigations. So you do your screening tests. So you do an overnight dexamethasone suppression test which comes back raised at 85 you then proceed onto a confirmatory test, the low dose dexamethasone suppression test, which comes back at 65 which is also high and your ACTH comes back more Axley. Um ACTH actually takes a while to come back which is why you do other investigations. Why did you wait for that piece of information? Um But when it, it has come back now. So the question is, what's your next step? I've got a question from Toler. Um I will explain that uh in a second about the differences between high and low dose dexamethasone suppression test. Perfect. So this question was just checking that I'm doing a reasonable job in teaching. So let's just talk about the high low dose and high dose Xmas expression test. So first of all, the low desk expression expression test, I'll just go back a few slides to go to that protocol is to confirm the diagnosis of diagnosis of excess cortisol. Just to prove that the patient has excess cortisol in the first place. High dose dexamethasone suppression test uses 2 mg instead of 20.5 mg. So we are using a higher dose, we use the same protocol. So the patient takes the tablet 66 AM every six hours for 48 hours. Now, the pituitary tumour respond to this level of dexa medicine and they do not produce a C T H. So they are suppressible with this high level of Dexa medicine. So the course of levels in the pituitary cause will be low. So it would be less than 50 or be 55. So there's at least partial suppression when it comes to a pituitary course. Now compare that with an ectopic ACTH. So you have a lung tumor which is turning out ACTH, it's not going to respond to any levels of Dexa medicine. Why? Because it hasn't got receptors to respond to it. It's a tumor. It has no differentiation, has no reason to respond to Dexa medicine. It's completely undifferentiated. It is doing something that it shouldn't be doing. Your adrenal adenoma is producing cortisol. So Dexa medicine doesn't have any effect on cortisol secretion directly. It has an effect at the hypothalamic pituitary level. And on crh and ACTH secretion, your adrenal adenoma is not affected by decks medicine levels either. So it's only your pituitary that will be affected at a higher level of Dexa medicine. So I hope that explains the differences between the indications of when you use the low Dexa medicine in the high Dexa medicine. The protocol is identical. You just use 0.5 mg in low dose dexamethasone suppression test and use 2 mg and high dose dexamethasone suppression test. Um And the interpretation is slightly different. I hope that answers your question. Please do ask them if there are any other questions that you would like to go to like me to go through? Perfect. So let's go back to the case. Um So we've all gone for an MRI pituitary um because that we've talked about the differences between high dose and low does. Now, this is a very nice memory pituitary um uh with nice arrow which has a huge lesion, a large pituitary tumor. Now, in real life, tumors that produce excess cortisol, aren't this big? Why? Because patients are symptomatic earlier. And number two, that nature or the natural progression of these conditions does not cause tumor's of this size. So usually the tumor's are quite small and you may not necessarily see them on imaging. So the question is what the imaging was inconclusive. How would you approach that? So, I've just put out a pole and I want to see if what your thoughts are. I'll give you a couple of minutes. I'm pleased to ask any further questions if you have them. Okay. So I think I've got, we've got enough responses. So I think majority of people are asking to repeat the ACTH. Um oh, it's changed again, re image repeat ACTH and inferior patrols, a sinus sampling. So reimage has got the least number of votes. Um So if the imaging quality was poor, then yes, obviously, that's, that's something to go forth. But just remember the MRI Pituitary. Um It's a, it's a hard um scan to achieve, you know, perfection on anyway, pituitary gland should be normally quite small. Um And it's with gadolinium. So it's there may not be extra benefit. Um Even if you got the repeat scan, it was we weren't too sure about a lesion or not. It wouldn't give you a definitive answer. So, only in rare cases or select cases, would you want to reimage a repeat ACTH. That's a reasonable thought. Um Depending on how level high the ACTH level was. Um but it may, wouldn't tell you the difference or wouldn't make you want to operate on this patient. Cause that's where we're heading, isn't it? We're wondering if, has this patient got a pituitary tumor that we can take out and solve their symptoms? It wouldn't give you the answer. Now, in fear patrols, a sinus sampling is a technique used in these cases where we're not sure they have a pituitary tumor as demonstrated by imaging and discussed in an MD tea. And what we can do is we can if you look at the image on the right. So that's what they've done is they've soon proposed the vessels onto a scan. Now, what I want you to just remember or is that you don't need to focus on exact protocol for it. But if you think about them put in a catheter at both sides of the pituitary to on one on left, on one on the right hand side by threatening up the in fewer proposal sinus. And that they also use a cannula peripherally and they take lots of blood samples for ACTH and Cortisol. We're mainly looking at the ACTH this time. And what we're trying to do is compare the ACTH levels from central to peripheral and from left to right now, patootie allusions are usually grow on one side to the either go on the left hand side or the right hand side, you being lucky to have to patootie lesion's and or a central lesion that has blood supply both sides. It's a beauty being lucky to have that situation. So you're always going to expect a slight difference between central versus peripheral or you should do and that should happen. That should be a normal physiology because the ACTH is being produced at the pituitary gland. So we're expecting the central ACTH should be much higher than the periphery ACTH. The reference ranges ranges for that vary. So I won't, don't want you to remember that. However, if it's not different or if the peripheral range is so much greater than the central range, it raised your suspicion of an ectopic production of ACTH. So either from a lung cause a renal cause, etcetera that tells you that you need to do further imaging of the rest of the body to look for this cause. But back to the, the pituitary gland, once you've established that the central is much higher than the peripheral and much higher than your reference ranges, what you're really looking for is if the left is it infinitely high than the right? Because normal physiology shouldn't be if the left is significant higher than the right, then that suggests that is, and you've got a suspicious tumor on the left hand side or some suspicious lesion on the left hand side that suggests you have a tumor on the left hand side, that's producing excess ACTH, causing the excess cortisol and causing cushions syndrome. So this, that's how you would identify that this patient has cushions disease. And that gives you the confidence to send this patient off for an operation. You can also look for other clues. So I had, I did suggest that repeating the ACTH is a reasonable answer because if you have profoundly high levels. Um So I have seen ectopic ACTH a few times and one thing I have noted is that sometimes they can be undetectable high. Um And you would have to dilute them, you can look for risk factors of other cancers. So, lung cancer, if they're a smoker or constitutional symptoms, if they've got a new cough as well, and finally, you are going to be treating the excess quarter because remember, we have already diagnosed him with Cushing's Syndrome. The main, we're just trying to work out where is it coming from? We just, we just need to get a handle on that and control the source. But if it's fight, proven to be very difficult with medical management to manage these patient's that maybe suggestive of an ectopic cause rather than a pituitary course. So the manager of a case too, in this case, we confirmed perpetuity cause of cushions. They had a pituitary lesion, we would check the other pituitary hormones, we would manage them medically in the first instance. And surgically ultimately would be transsphenoidal surgery. Um This patient tend to do really well. They need um replacement, of course, for all the pituitary hormones depending on how old they are, but they don't need for the food. Of course, because the adrenals are still intact, but they would obviously need a steroid card and long term follow up. These are my references um in terms of looking at protocols for tests. If you're typing ended Bible into Google, that's a great place to get patient information, leaflets and also information for doctors and how you conduct these tests. Um There's also a great resource on the endocrine society about talking about the pitfalls of tests as I've briefly outlined in this presentation and I welcome any questions or any feedback or any thoughts that you would like answering. Thank you so much for listening. Joining me today, I'll wait around if there are any further questions or thoughts that people want to ask. Um um I'm also very happy for to a mute people if they want to ask the question directly. Oh, and I hope I answered your question just as people are leaving. Just remember the next week's session. Um It's postponed. So we have a talk on the 16th of February on thyroid function test and how to interpret them. I'm sure be an excellent talk um from a brilliant register at the Royal London. Um So please do join us for the next session. I will put post the link in, in the chat.